Process for the preparation of steroidal 1,4-dienes unsubstituted in the 3-position



United States Patent 3,479,340 PROCESS FOR THE PREPARATION OF STEROIDAL1,4-DIENES UNSUBSTITUTED IN THE 3-POSITION Richard W. Rees, St. Davids,Theodore J. Foell, King of Prussia, and Herchel Smith, Wayne, Pa.,assignors to American Home Products Corporation, New York, N.Y., acorporation of Delaware No Drawing. Filed Aug. 1, 1967, Ser. No. 657,507Int. Cl. C07c 167/00, 173/00; A61k 27/00 US. Cl. 260239.55 10 ClaimsABSTRACT OF THE DISCLOSURE Novel steroidal 1,4-dienes unsubstituted inthe 3-position (I), which are hormonally-active, are prepared by a newprocess comprising selectively with alkali metals or alkaline earthmetals in excess in a liquid amine a 3-di- (lower)alkylmercaptole of a1,4-diene steroid (11) until conversion of the3-di(lower)alkylmercaptole group to a 3-methylene group is substantiallycomplete.

This invention relates to the preparation of new 1,4- diene steroidshaving an unsubstituted 3-postion. The steroids produced in accordancewith this invention show steroid hormonal activity in animals as shownby standard test procedures and are useful for the preparation of other1,4-diene steroids having hormonal activity.

The compounds provided by the process of this invention are 1,4-dienesteroids having an unsubstituted 3-position of Formula I:

wherein R is lower alkyl, particularly methyl, R R and R are hydrogen orlower alkyl and X is an organic radical of at least 11 carbon atoms soarranged as to complete a cyclopentanoperhydrophenanthrene nucleus.

By(lower)alkyl in this specification is meant such radical having from 1to about carbon atoms.

Special mention is made of a class of preferred steroids of thisinvention: these are steroidal 1,4 diene compounds of Formula I whereinR is methyl, R and R are hydrogen, R is hydrogen or methyl and X issubstituted with hydrogen, hydroxy, alkanolyloxy, keto, carbalkoxy,cyano, alkyl, alkenyl, alkynyl, haloalkynyl, methylene, ethylidene,lactone, ether, ketal, spiroketal, halogen or unsaturated linkages. Theterms alkyl, alkenyl, alkynyl, and haloalkynyl include straight andbranched chain hydrocarbon groups containing from about one to aboutfive carbon atoms and single, double or triple bonds, as the case maybe. Illustrative groups are, for example, methyl, ethyl, n-propyl,n-butyl, t-butyl, n-pentyl, 2- ethylpropyl, and olefinic and acetylenicderivatives thereof. Alkanoyloxy and carbalkoxy groups include thosecontaining from about 1 to about 18 carbon atoms in straight or branchedchain arrangements, illustrative members of which are, for example,acetoxy, n-propionoxy, t-butyroxy, n-dodecanolyloxy, n-octadecanoyloxy,carbomethoxy, carboethoxy, carbo-n-propoxy, carbo-t-butoxy,carbo-n-dodecyloxy, carbo-n-octadecyloxy, and the like. Halogen includesfluorine, chlorine, bromine and iodine. Ketals, spiroketals and lactonespreferably contain, respectively, from about 2 to about "ice 8 carbonatoms; from about 2 to about 8 carbon atoms and from about 2 to about 4carbon atoms.

The present invention particularly contemplates a class of compounds ofFormula I hereinabove wherein the substituted organic radical X includes11 carbon atoms arranged as follows:

and R is hydrogen or lower alkyl. Examples are androsta-1,4-dienes (Rand R are methyl) and IO-methylgona- 1,4-dienes (R is methyl, R ishydrogen).

Particularly preferred are those steroids wherein X is a radical of thestructure wherein R is hydrogen or (lower)alkyl, particularly methyl; Ais a divalent linkage selected from ketalized carbonyl,

0:0 and 0 R being hydrogen or an acyl radical of an organic carboxylicacid having from 1 to 18 carbon atoms and R is hydrogen,(lower)alkyl,(lower)alkenyl,(lower) alkynyl or chloro(lower)alkynyl,especially methyl, ethyl, vinyl, ethynyl or chloroethynyl; and B is adivalent linkage selected from CH2, 0 0 or C and R is hydrogen or(lower)alkyl. Examples are pregnal,4-dienes (R and R are methyl) and17-ethyl-10-methylgona-1,4-dienes (R is methyl, R is hydrogen).

Particularly preferred steroids of this latter class are those ofFormula Ia:

(Ia) CHAR.

wherein R is (lower) alkyl, R R and R are hydrogen or (lower)alkyl; R ishydrogen or (lower) alkyl, particu- R" is oxo(ket0), H(OH) or H(OR Rbeing a hydrocarbon acyl group of up to 18 carbon atoms; R and Rindependently, are hydrogen, hydroxyl or a hydrocarbon carboxylicacyloxy group of up to 18 carbon atoms; R is hydrogen or (lower) alkyl,especially methyl; R is hydrogen or fluorine; and -(lower alkylene),preferably ethylene, ketal derivatives of said compounds wherein R isketo, l7a,2l-(lower)alkylenedioxy, preferably isopropylidenedioxy,derivatives of said compounds wherein R and R are hydroxy, and17ot,20;20,21-bis[lower(alkylenedioxy)], preferably methylene dioxy,derivatives of said compounds wherein R and R are hydroxy and R' is oxo.These preferred steroids wherein R represents hydrogen are powerfulprogestational agents with oral activity. In addition they haveanti-androgenic, anti-gonadotrophic or anti-estrogenic properties or areuseful in fertility control. Furthermore, they may be used in thetreatment of premenstrual tension. When applied topically, oradministered orally the compounds are useful in the treatment of acne.

The compounds of this embodiment wherein R is not hydrogen and Brepresents a fi-hydroxymethylene group are valuable cortical hormoneswith anti-inflammatory, low catabolic, glycogenic and thmolyticactivities. In addition, they are anti-androgenic, anti-gonadotrophic orantiestrogenic hormones. Furthermore, they have activity, includingtopical activity, in skin disorders such as psoriasis, allergicdermatitis and the like.

Illustrative are pregna-1,4-dienes and more particularly,

17a-20;20,2 l-bis- (methylenedioxy) -1 l-hydroxypregna- 1,4-diene;

1 1,17a-2l-trihydroxypregna-1,4-dien-20-one;

21-hydroxypregna-1,4-dien-20-one, ZO-ethylene ketal;

2 1 -hydroxypregna- 1,4-dien-20-one;

17a-21-dihydroxypregna-1,4-dien-20-one, ZO-ethylene ketal;

17a-21-dihydr0xypregna-1,4-dien-20-one;

ZOE-hydroxypregna-1,4-diene;

pregna-1,4-dien-20-one;

9a-fluoro-1 6a-methyl- 1711,20 ;20,2 l bis- (methylenedioxy)1lfi-hydroxypregna-1,4-diene;

9a-fluoro-16a-methyl-11,8,17a,21-trihydroxypregna-1,4-

dien-20-one;

9u-fiuoro-1 1p, 16a,17a,2l-tetrahydroxypregna-l,4-dien- 20-one;

6a-methyl-11B,17a,21-trihydroxypregna-1,4-dien-20-0ne;

2,6a-dimethyl-11 8,l7ot-21-trihydroxypregna-1,4-

dien-ZO-one;

9a-fluoro-6a-methyl-11p,17ot-21-trihydroxypregna-1,4-

dien-ZO-one;

9a-fluoro-1 15,17ot-21-trihydroxypregna-1,4-dien-20-one;

t-flllOI'O-1 1,8-hydroxy-17a,20;20,21-bis(methylenedioxy)-pregna-1,4-diene,

and the like. Special mention is made of 17a,20;20,21-bi$(methylenedioxy) pregna 1,4 dien 11B ol; 1711,20; 20,21bis(methylenedioxy) 9a fluoro 16oz methylpregna 1,4 dien 11,8 01 andl7a,20,20,21 bis(methylenedioxy)9a fluoro pregna 1,4 dien 11,8 01, whichare highly potent anti-inflammatory agents.

DESCRIPTION OF THE INVENTION The instant invention contemplates aprocess for the preparation of compounds of Formula I hereinabove, whichprocess comprises, if required, protecting sensitive groups in otherportions of the molecule, selectively hydrogenolyzing a3-di(lower)alkylmercaptole 1,4- diene steroid of Formula II:

wherein R, R R R and X are as above defined for Formula I and R is(lower)alkyl, preferably methyl, until conversion of the3-di(lower)alkylmercaptole group to a methylene group is substantiallycomplete; if required, regenerating the protected sensitive groups; andrecovering said 1,4-diene having an unsubstituted 3-position; then, ifrequired, oxidizing, reducing, alkylating, esterifying or hydrolyzingthe compound thus formed.

Of course, as will be well understood by those skilled in the art, theterm selectively hydrogenolyzing means replacing the3-di(lower)alkylmercaptole group with a B-methylene group withoutirreversibly degrading the rest of the steroid molecule. Many means areknown to accomplish this including protecting sensitive groups in otherportions of the molecule and regenerating them by subsequent operations.For example, the 17-ketol group in corticosteroids is protected byforming a diethylene ketal or the like; a 17,20;20,2l-bismethylenedioxygroup; or a 17,21-diacetal with subsequent reduction of the carbonylfunction. After having protected the dihydroxyacetone side chain, the 3-di(lower)alkylmercaptole function is hydrogenolyzed with Raney nickel oran alkali metal or an alkaline earth metal in a liquid amine, or anobvious chemical equivalent thereof, according to the instant process,and the pregna-1,4-diene is obtained. The protected 17-dihydroxy-aoetonegroup is regenerated by treatment with acid for instance as will befully described hereinafter. If a 17,21-acetal is used as a protectinggroup, the 20-alcohol is reoxidised, with chromic oxide, e.g. inpyridine or an obvious chemical equivalent thereof, before removal ofthe acetal with acid. Furthermore, if the substituent in the S-memberedD ring constitutes or comprises only a 17- or a 20 ketone group, theketone group can be protected by a conversion to an ethylene ketal or itcan be reduced prior to the cleavage reaction and subsequently oxidisedwith CrO or an obvious chemical equivalent thereof. A acyloxy group willundergo conversion during hydrogenolysis, especially with an alkalimetal or an alkaline earth metal in a liquid amine, to a hydroxy groupbut it may, if required, be re-esterified. The procedures will be fullyexemplified hereinafter.

As mentioned, also contemplated by the instant invention are embodimentscomprising the novel selective hydrogenolysis of a3-di(lower)alkylmercaptole group including subsequent, optional, stepsof oxidising, reducing, alkylating, esterifying, and hydrolysingfunctional groups in radiacl X. For example it is contemplated toconvert a hydroxymethylene group to a keto group by use of chromic acidor an Oppenauer reagent, such as aluminum isopropoxide. Where there is acarbonyl group in X which it is desired to convert to a hydroxymethylenegroup, this is done with a carbonyl reducing agent, for example aborohydride to reduce a 17-keto, a 20-keto or an ll-keto group. Where itis desired to convert an alkylenedioxymethylene group or abis-methylenedioxy group, and the like to correspondingcarbonyl-containing groups, the latter are obtained by hydrolysis underthe acid conditions necessary to remove the ketal groups. Where it isdesired to convert a hydroxymethylene or a hydroxy(alkyl-substituted)methylene group to corresponding acyloxymethylenegroups, the latter are obtained by esterification with an acylatingagent. Esterification can be carried out by any suitable acylatingagent, for instance an acid anhydride, acyl halide, or an obviouschemical equivalent thereof. If it is desired to convert a keto group toan hydroxy (alkyl-substituted) methylene group (alkyl in this senseincluding saturated (lower) alkyl, (lower)alkenyl, (lower)alkynyl orchloro (lower)alkynyl), the compound with former group is treated withan alkyl magnesium halide or an alkyl lithium compound; in all cases thereagents are preferably brought together in a suitable solvent mediumand heat is applied as necessary.

The present invention particularly contemplates the preparation of a1,4-diene compound of Formula I by a process which comprises selectivelyhydrogenolyzing the 3-di(lower)alkyl mercaptole group in a 1,4-diene ofFormula II with Raney nickel catalyst preferably in the presence of asolvent such as a (lower) alkanol, e.g., ethanol, methanol, and thelike, or an aromatic hydrocarbon solvent such as benzene, xylene and thelike and preferably at a temperature corresponding to the refluxtemperature of the mixture. Raney nickel, also known as Raney catalyst,is a well known and useful form of nickel metal. It is a highly-active,finely-divided nickel catalyst, prepared by dissolving the aluminum outof an alloy comprising Ni 30, Al 70, with alkali. The preparation anduse of Raney nickel is described in the reference collected by E. Petitand E. V. Tamelin, in Organic Retactions, volume 12, John Wiley andSons, Inc., New York, p. 356, 1962.

According to one manner of carrying out this embodiment the3-diloweralkylmercaptole 1,4-diene steroid of Formula II is dissolved orsuspended in about 50 parts by weight of an organic solvent, such asmethanol, about parts by weight of Raney nickel per part by weight ofthe steroid is added and the mixture is refluxed until conversion of the3-di(lower)alkylmercaptole group to a 3-methylene group is substantiallycomplete. It is found that 5 hours of refluxing is suitable in mostinstances although shorter or even longer times can be used. The productof Formula I is recovered by any conventional manner. For example, themixture can be cooled to about C., the catalyst removed by filtrationand washed with an organic solvent. The combined filtrate and washingscan be evaporated to leave the product as a residue. If desired, theresidue can be further purified by re-crystallization or bychromatography on an appropriate adsorbent, such as silica gel andelution with a solvent, such as a mixture of benzene and ethyl acetate.These techniques will be exemplified in detail hereinafter.

This invention also contemplates among its specific embodiments thepreparation of a 1,4-diene compound of Formula I by a process whichcomprises selectively hydrogenolyzing the 3-di(lower)alkylmarcaptolegroup in a 1,4-

diene of Formula II with a catalyst comprising an alkali metal or analkaline earth metal in a liquid amine, preferably in the presence of analkanol. Suitably, and preferably, the alkali metal is lithium and theliquid amine is ammonia. However, especially useful catalysts alsoinclude the alkali metals, other than lithium, or alkaline earth metals,especially calcium, and the especially useful liquid amines are ammoniaor low molecular weight amines, preferably ethylamine.

According to one manner of carrying out this embodiment, the3-di(lower)alkylmercaptole 1,4-diene steroid of Formula II is dissolvedor suspended in about parts by weight of the liquid amine, to whichpreferably about 20 parts by weight, based on the steroid, of a solventsuch as tetrahydrofuran has been added. The alkali metal or alkalineearth metal, such as lithium or calcium, is added piecemeal until anexcess is present-if lithium is used, a blue color will persist. Thereaction mixture is kept until formation of a 3-methylene group (productFormula I) is complete; thirty minutes is usually ample. The product canbe recovered in any convenient way. One useful means is to addcautiously ammonium chloride, then hot water, to decompose the unreactedmetal and to drive oif the amine. The mixture can then be extracted witha solvent such as chloroform; evaporation of the solvent leaves theproduct as a residue. It can be purified, if desired, byrecrystallization from a solvent, such as methanol, or by chromatographyin a known manner, such as on a silica gel adsorbent, eluting with asolvent mixture, such as a mixture of benzene and ethyl acetate.

Starting materials, the 3-di(lower)alkylmercaptoles of 1,4-dienesteroids (Formula II) are prepared according to techniques disclosed forexample, in detail in D. E. Ayer, U.S. 3,261,854, or are readilyderivable therefrom. In essence, a solution of a A -3-oxosteroid in adialkylformamide is cooled to about 0 C., and iodine and an alkane thioladded. The mixture is allowed to stand for about 3 to 5 days at atemperature of about 25 C. Higher temperatures will cause the reactionto be completed faster, but the use of a sealed reaction system then isrequired. After the reaction is complete, compounds of Formula II can berecovered by diluting the reaction mixture with ice water and filteringthe precipitate. They can be purified by recrystallization if desired.The A 6- oxosteroids used to make the compounds of Formula II arereadily available by well-known synthetic pathways. In addition to thesources cited in the above-mentioned Ayer patent, A -3-oxosteroids canbe prepared from the A -3-oxosteroids shown, for example, in G. V.Baddeley, H. Carpio and I. A. Edwards, J. Orig. Chem., 31, 1026 (1967);and in U.S. patent application Ser. No. 626,953, filed Mar. 30, 1967, byintroducing a double bond in the 1,2-position according to conventionalprocedures, such as by treatment with dichloro-dicyanoquinone, seleniumdioxide or by microbial fermentation. Other useful A- 3-oxosteroids aredescribed by W. S. Allen, H. M. Kissman, S. Maner, I. Ringler and M. J.Weiss, J. Med. Pharm. Chem., 5, 133 (1962) and by Boylor and Sarett inU.S. 2,888,457.

It will be apparent from the disclosure herein to those skilled in theart that for the purposes of this invention, certain of the atoms of the3-di(lower)alkylmercaptole 1,4-diene steroidal starting materials can besubstituted with groups which do not interfere with the subsequentreactions. Thus included within the scope of this invention areandrosta-1,4-dienes, pregna-l,4-dienes, lO-alkylgona-1,4-dienes andcholesta-1,4-diene derivatives.

When the starting compounds are substituted as hereinbefore designated,it will be apparent herefrom to those skilled in the art of chemistrythat the final product formed in the processes of the invention willbear correspondingly the same or related substituents. Thus, for theprocesses of the invention and for the product of the invention producedthereby, such groups are the full equivalents of the invention asparticularly claimed.

When the steroidal 1,4-dienes prepared by the process of this inventionare employed as hormonal agents, they may be administered alone or incombination with pharmaceutically acceptable carriers, the proportion ofwhich is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard pharmaceuticalpractice. For example, they may be administered orally in the form oftablets or capsules containing such excipients as starch, milk sugar,certain types of clay and so forth. They may be administeredsublingually in the form of troches or lozenges in which the activeingredient is mixed with sugar and corn syrups, flavoring agents anddyes; and then dehydrated sufliciently to make it suitable for pressinginto a solid form. They may be administered orally in the form ofsolutions which may contain coloring and flavoring agents or they may beinjected parenterally, that is intramuscularly, intravenously orsubcutaneously. For parenteral administration they may be used in theform of a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the therapeutic agents prepared by the instant processwill vary with the form of administration and the particular compoundchosen. Furthermore, it will vary with the particular subject undertreatment. Generally, treatment is initiated with small dosagessubstantially less than the optimum close of the compound. Thereafter,the dosage is increased by small increments until the optimum effectunder the circumstances is reached. It will generally be found that whenthe composition is administered orally, larger quantities of the activeagent will be required to produce the same effect as afsmaller quantitygiven parenterally. In general, the compounds of this invention are mostdesirably administered at a concentration level that will generallyafford effective results without causing any harmful or deleterious sideeffects and preferably at a level that is in the range of from about 0.1mg. to about 400 mg. per day, although as aforementioned variations willoccur. However, a dosage level that is in the range of from about 0.5mg. to about 100 mg. per day is most desirably employed in order toachieve effective results.

DESCRIPTION OF THE PREFERRED EMBODIMENT The following examplesillustrate the best mode contemplated of using the claimed processes ofthe invention and of the manner of making the claimed products of theinvention.

Example 1 17a,2l-dihydroxypregna-l,4-dien-20-one.17a,21dihydroxy-1,4-pregnadien-3,20-dione, 3-dimethylmercaptole, prepared asin the procedure of Example 9 of U.S. Patent 3,261,854, 0.5 g., isdissolved in 30 ml. of ethanol and refiuxed for hours with 5.0 g. ofRaney nickel catalyst [Organic Syntheses, vol. 21, John Wiley and Sons,Inc., New York, p. (1941)]. The mixture is cooled to about C., the Raneynickel is removed by filtration and washed thoroughly with ethanol. Thefiltrate is combined with the washings and evaporated to dryness in avacuum leaving the product as a residue. The residue is chromatographedon silica gel and eluted with a mixture of benzene and ethyl acetate.Recrylstallization of the material from methanol provides crystals ofproduct, M.P. 112120 C.

Example 2 17 8 hydroxyandrosta 1,4 dien diene.-17;8hydroxyandrosta-1,4-dien-3-one, 3-dimethylmercaptole, 0.5 g., isselectively catalytically hydrogenolyzed by the procedure of Example 1and the product, M.P., 130132.5 C., is obtained.

Example 3 Androsta 1,4 dien 17 one, 17 ethylene ketal.-Androsta-1,4-dien-l7-one, 17-ethylene ketal, B-dimethylmercaptole, 0.5g., is selectively catalytically hydrogenolyzed by the procedure ofExample 1 and the product is recovered as an oil. The infrared spectrumconforms to the expected structure.

The androsta-1,4-dien-17-one, 17-ethylene ketal, 1.5 g., is dissolved in25 ml. of methanol and stirred for 3 hours at room temperature with 2.5ml. of a mixture of cone. HCl (37.5 ml.) and water (12.5 ml.). A slightexcess of saturated NaHCO solution and water is then added and theproduct extracted into CHCI The chloroform solution is washed withwater, dried over Na SO and the solvent is removed in vacuo to give theandrosta-1,4-dien- 17-one as an oily solid,

1.0 g. xggf 3.44, 3.48, 3.52, 5.75

Example 4 Androsta 1,4 dien 17 one.Androsta 1,4 diene- 3,17-dione,3-dimethylmercaptole, 0.5 g., is selectively catalyticallyhydrogenolyzed by the procedure of Example 1 and the product, withproperties described in Example 3, is obtained.

Example 5 170a ethynyl 17B hydroxyandrosta 1,4 diene.- 170; ethynyl 17,8hydroxyandrosta 1,4 diene 3- one, 3-dimethylmercaptole, 0.5 g., isselectively catalytically hydrogenolyzed by the procedure of Example 1and the product, M.P., -96 C., is obtained.

Example 6 17a chloroethynyl 17,6 hydroxyandrosta 1,4- diene.-l7achloroethynyl 17B hydroxyandrosta 1,4- dien-3-one, B-dimethylmercaptole,0.5 g., is selectively catalytically hydrogenolyzed by the procedure ofExample 1 and the product is obtained.

Example 7 17a,20;20,21 bis(methylenedioxy) 11B hydroxypregna 1,4diene.17a,20;20,21bis(methylenedioxy)-1lfi-hydroxypregna-1,4-dien-3-one, 3dimethylmercaptole, 0.5 g., is selectively catalytically hydrogenolyzedby the procedure of Example 1 and the product, M.P., 186188 C., isobtained.

Example 8 11B,17u,21 trihydroxypregna 1,4 dien 20 one.-- 11,8,17a,21trihydroxypregna 1,4 dien 3,20 dione, 3-dimethylmercaptole, 0.5 g.,prepared as in Example 9 of U.S. 3,261,854 is selectively catalyticallyhydrogenolyzed -by the procedure of Example 1 and the product, M.P.,108-116 C., is obtained.

Example 9 21 hydroxypregna 1,4 dien 20 one, 20 ethylene ketal.2lhydroxypregna 1,4 diene 3,20 dione, 20- ethylene ketal,3-dimethylmercaptole, 0.5 g., is selectively catalyticallyhydrogenloyzed by the procedure of Example 1 and the product, M.P., 117C., is obtained.

Example 10 21 hydroxypregna 1,4 dien 20 one.21hydroxypregna-l,4-diene-3,20-dione, 3 dimethylmercaptole, 0.5 g., isselectively catalytically hydrogenolyzed by the procedure of Example 1and the product, M.P., 113- 119 C., is obtained.

Example 11 :,21 dihydroxypregna 1,4 dien 20 one, 20- ethylene ketal.17x,2l dihydroxypregna 1,4 diene 3,20-diene, 20-ethylene ketal,S-dimethylmercaptole, 0.5 g., is selectively catalyticallyhydrogenolyzed by the procedure of Example 1 and the product, M.P.,128-160 C., is obtained.

Example 12.

17oc,21 dihydroxypregna 1,4 dien 20 one.-

17a,21 dihydroxypregna 1,4 diene 3,20 dione, 3-'

dimethylmercaptole, 0.5 g., is selectively catalytically hydrogenolyzedby the procedure of Example 1 and the prdouct, M.P., 112-120 C., isobtained.

Example 13 205 hydroxypregna 1,4 diene.-20Ehydroxypregna-1,4-dien-3-one, 3-dimethylmercapto1e, is selectivelycatalytically hydrog'enolyzed by the procedure of Example 1 and theproduct, M.P., 138-141 C., is obtained.

Example 14 Pregna 1,4 dien 20 one.-Pregna 1,4 diene- 3,20-dione,3-dimethylmercaptole, 0.5 g., is selectively catalyticallyhydrogenolyzed by the procedure of Example 1 and the product, M.P.,l31-137 C., is obtained.

Example 15 9a fluoro 115 hydroxy-17a,20;20,2l-bis(methylenedioxy)-pregna1,4 diene.9a fluoro 115 hydroxy- 17u,20;20,21-bis(methylenedioxy)-pregna1,4 dien-3- one, 3-dimethylmercaptole, 0.5 g., is selectivelycatalytically hydrogenolyzed by the procedure of Example 1 and theproduct, M.P., 168-174 C., is obtained.

Example 17 9oz fluoro 11B,16oc,l7ot,2l tetrahydroxy-pregna-1,4-dien--one.9ot fluoro 11,8,16a,17 00,21tetrahydroxypregna-l,4-diene-3,20-dione, B-dimethylmercaptole, 0.5 g.,is selectively catalytically hydrogenolyzed by the procedure of Example1 and the product is obtained.

Example 18 6a methyl 11fl,17a,21 trihydroxypregna 1,4 dien- 20-one.--6amethyl 1lfl,l7oc,2l trihydroxypregna-l,4- diene-3,20-dione,3-dimethylmercaptole, 0.5 g., prepared as in Example 9 of US. 3,261,854,is selectively catalytically hydrog-enolyzed by the procedure of Example1 and the product is obtained.

Example 19 2,60; dimethyl 11fi,l7a,2l trihydroxypregna 1,4-dien-20-one.-2,6a dimethyl 11p,17a,21trihydroxypregna-1,4-diene3,20-di0ne, 3-dimethylmercaptole, 0.5 g.,

is selectively catalytically hydrogenolyzed by the procedure of Example1 and the product is obtained.

Example 20 90c fluoro 6a methyl 11B,l7u,21 trihydroxypregna 1,4 dien 200I16.9a fluoro 6oz methyl- 11,8,17a,21-trihydroxypregna 1,4diene-3,20-dione, 3-dimethylmercaptole, 0.5 g., prepared as in Example 9of US. 3,261,854, is selectively catalytically hydrogenolyzed by theprocedure of Example 1 and the product is obtained.

Example 21 10 Example 23 The procedure of Example 1 is used toselectively catalytically hydrogenolyze 0.5 g. each of the following3-di(lower)alkylmercaptole 1,4-diene steroids:

l7fl-hydroxy-17a-methylandrosta-1,4-dien-3-0ne,

3-dimethylmercaptole;13fi-ethyl-17u,21-dihydroxygona-1,4-diene-3,20-dione,

3-dimethylmercapto1e; 1 1 8,17fldihydroxy-17a-methy1androsta-1,4-dien-3-one,

3-di-n-pentylmercaptole;17u,21-dihydroxy-10-ethyl-13-methylgona-1,4-diene-3,20-

dione, 3-dimethylmercaptole;170:,2I-dihydroxy-1-methylpregna-1,4-diene-3,20-dione,

3-dirnethylmeroaptole;17u,21-dihydroxy-4-methylpregna-1,4-diene-3,20-dione,

B-dimethylmercaptole; and17u,2l-dihydroxy-lO-methyl-13B-n-pentylgona-1,4-

diene-3,20-dione, 3-dimethylmercaptole.

There are obtained:

17/3-hydroxy- 17a-methy1androsta-1 ,4-diene; 13 [i-ethyl-17a,2l-dihydroxygona-l ,4-dien-20-one; 11B,17/3-dihydroxy-17a-methylandr0sta-1,4-diene; 17 a,2 l-dihydroxy-IO-ethyl- 1 3-methylgona-1,4-dien- 20-one; 17 a,2l-dihydroxyl-methylpregna-l ,4-dien-20-one;17a,21-dihydroxy-4-methylpregna- 1,4-diene-20-o11e; andl7a,2l-dihydroxy- IO-methyl-1BIB-n-pentylgona-l,4-dien- 20-one.

Example 24 17,8 hydroxy 17a methyla-ndrosta 1,4 diene. 17B hydroxy 17amethylandrosta 1,4 dien 3 one, 3-dimethylmercaptole, 0.5 g., isdissolved in 50 ml. of liquid ammonia and 10 ml. of tetrahydrofuran.Lithium metal is added piecemeal until a blue color persists and themixture is stirred for 30 minutes more. The mixture then is decomposedwith the cautious addition of ammonium chloride followed by hot water.Extraction of the mixture with chloroform, concentrating the extract andchromatographing the residue on silica gel provides the product.Recrystallization from hexane provides crystals, M.P., -80 C.

The reaction is repeated substituting liquid ethylamine for ammonia.Substantially the same results are obtained.

The reaction is repeated substituting calcium for the lithium.Substantially the same results are obtained.

Example 25 The procedure of Example 24 is used to selectivelyhydrogenolyze 0.5 g. each of the following 3-di(lower)- alkylmercaptolesteroids:

17 ,B-hydroxyandrosta-1,4-dien-3-one, 3-dimethylmeroaptole;

and-rosta-1,4-diene-3,l7dione, 17-ethylene ketal,

3-dimethylmercaptole;

17 a,20;20,21-bi$ (methylenedioxy) -1 1 fl-hydroxypregna-1,4-dien-3-one, S-dimethylmercaptole;

17 B-hydroxypregna-1,4-dien-3 ,20-di0ne, 20-ethylene ketal,

3-dimethylmercaptole;

17a,2 l-dihydroxypregna-l ,4-diene-3,20-dione, 20-ethylene ketal,3-dimethylmercaptole;

ZOg-hydroxypregna-l,4-dien-3-one, dimethylmercaptole;

9a-fluoro-1lit-hydroxy-17a,20;20,21-bis(methylenedioxy)-pregna-1,4-dien-3-one, S-dimethylmercaptole; and

1 1p,17 8-dihydroxy-17u-methylandrosta-1,4-dien-3-one,

3-di-n-pentylmercaptole.

There are obtained:

1 7a-hydroxyandrosta-1,4-diene;

androsta-1,4-dien-l7-one, 17-ethylene ketal;

17a,20;20,21 bis(methylenedioxy) 11,8 hydroxypregna- 1,4-diene;

wherein R is lower alkyl; R R and R are hydrogen or lower alkyl; and Xis an organic radical of at least 11 carbon atoms so arranged as tocomplete a cyclopentanoperhydrophenanthrene nucleus; which comprisesselectively hydrogenolyzing a 3-di(lower)alkylmercaptole 1,4- dienesteroid of the formula:

I R R R'S X wherein R, R R R and X are as above defined and R is (lower)alkyl, in the presence of an alkali metal or an alkaline earth metal ina liquid amine until conversion of the 3-di(lower)alkylmercaptole groupto a methylene group is substantially complete; and recovering said1,4-diene having an unsubstituted 3-position.

2. A process as defined in claim 1, wherein R and R are methyl and R andR and R are hydrogen.

3. A process as defined in claim 1 wherein the alkali metal is lithiumand the liquid amine is amonia.

4'. A process as defined in claim 3 wherein17p-hydroxy-l7a-methylandrosta-1,4-diene is prepared by selectivelyhydrogenolyzing 17fi-hydroxy-l7a-methylan-drosta- 1,4-dien-3-one,3-dimethylmercaptole.

5. A process as defined in claim 1 wherein 17B-hydroxyandrosta-1,4-dieneis prepared by selectively hydrogenolyzingl7B-hydroXyandrosta-1,4-diene-3-one, 3-dimethylmercaptole.

6. A process as defined in claim 1 wherein androsta- 1,4-dien-17-one,17-ethylene ketal is prepared by selectively hydrogenolyzingandrosta-1,4-diene-3,17-dione, l7- ethylene ketal,3-dirnethylmercaptole.

7. A process as defined in claim 1 wherein 17u,20;20,2lbis(methylenedioxy)-llfl-hydroxypregna-l,4-diene is prepared by selectivelyhydrogenolyzing 17a,20;20,21-bi$- (methylenedioxy) 1113 hydroxypregna1,4 dien 3- one, 3-dimethylmerca-ptole.

8. A process as defined in claim 1 wherein17u,21-dihydroxypregna-l,4-dien-20-one, ZO-ethylene ketal is prepared byselectively hydrogenolyzing 17a,21-dihydroxypregnal,4-diene-3,20-dione,20-ethylene ketal, 3-dimethylmercaptole.

9. A process as defined in claim 1 wherein 20-hydroxypregna-l,4-diene isprepared by selectively hydrogenolyzing20g-hydroxypregna-1,4-dien-3-one, 3-dimethylmercaptole.

10. A process as defined in claim 1 wherein 9a-fiuorollfi hydroxy17oz,20;20,21 bis(methylenedioxy)pregna-1,4-diene is prepared byselectively hydrogenolyzing c fiuoro 11,8 hydroxy 17a,20;20,21'bis(methylenedioxy)pregna-1,4-dien-3-one, 3-dimethylmercaptole.

References Cited UNITED STATES PATENTS 7/1968 Shroif 260-397.4 9/1968Cross 260-3974 ELBERT L. ROBERTS, Primary Examiner

